Zamaporvint
RXC004, PHASE 2
1H-IMIDAZOLE-1-ACETAMIDE, 5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-
5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-1H-IMIDAZOLE-1-ACETAMIDE
UNII
M56M7CHN8E |
| Molecular Weight | 439.39 |
|---|---|
| Formula | C21H16F3N7O |
| CAS No. | 1900754-56-4 |
Zamaporvint (RXC004) is an orally active and selective inhibitor of Wnt. Zamaporvint targete membrane-bound o-acyltransferase Porcupine and inhibited Wnt ligand palmitoylation, secretion, and pathway activation. Zamaporvint displays a favorable pharmacokinetic profile and shows potent antiproliferative effects in Wnt ligand-dependent colorectal and pancreatic cell lines. Zamaporvint possesses multiple antitumor mechanisms and can be used in cancer research.
SCHEME
PATENT
Redx Pharma PLC
WO2016055786
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016055786&_cid=P22-M13AHC-85069-1
Example 9: 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2- yl-2-pyridyl)acetamide
To a stirred solution of lithium 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.04g, 3.57mmol) and 5-pyrazin-2-ylpyridin-2-amine (738mg, 4.29mmol) in THF (35mL) was added Ν,Ν-diisopropylethylamine (1.56mL, 8.93mmol) and propylphosphonic anhydride (6.38mL, 10.7mmol) and the resulting solution heated to 70°C. Reaction was monitored by LCMS and after 2 hrs further propylphosphonic anhydride (2.13mL, 3.57mmol) and N,N-diisopropylethylamine (0.6mL) were added the solution was allowed to cool to room temperature and stirred over the weekend. The solution was diluted with water and EtOAc and partitioned. The aqueous was washed with EtOAc (x2) before the combined organics were washed with brine. Product precipitated and was isolated by filtration and loaded onto a MeOH primed 10g SCX cartridge, washing with MeOH and eluting with 1 M NH3 MeOH solution. The ammonia methanol solution was concentrated to dryness in vacuo to afford an off white solid which was then dried in a vacuum oven for 2hrs. The organics were separated from the filtrate, dried (sodium sulphate), filtered and concentrated to dryness in vacuo to afford a light brown foam containing product of ~95% purity. This was dissolved in DCM and purified by flash column chromatography (25g SiO2, 70-100% EtOAc in heptane, then 0-5% MeOH/EtOAc). Appropriate fractions were combined and concentrated to dryness in vacuo to afford an off white solid. The solids were combined to give 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (1.22g, 2.77mmol, 78% yield) as an off white solid.
MS Method 2: RT: 1.45 min, ES+ m/z 440.1 [M+H]+
1H NMR (400MHz, DMSO) δ/ppm: 11.27 (bs, 1 H), 9.32-9.33 (d, J=1.6Hz, 1 H), 8.70-8.75 (m, 2H), 8.64-8.65 (d, J=2.4Hz, 1 H), 8.54-8.58 (dd, J=2.4, 8.8Hz, 1 H), 8.17-8.19 (d, J=9.2Hz, 1 H), 8.09 (s, 1 H), 7.92-7.94 (d, J=4.4Hz, 1 H), 7.85 (s, 1 H), 5.12 (s, 2H), 2.45 (s, 3H).
/////////Zamaporvint, RXC004, RX C004, PHASE 2